The figure shows Pittsburgh Compound-B (PiB) positron emission tomography (PET) images from a cognitively normal control, an Alzheimer's disease (AD) patient and a Mild Cognitive Impairment (MCI) patient. The images are not shown in the order listed and are intentionally not labeled to make the point that the presence, amount and regional distribution of fibrillar amyloid-beta (A) deposits in the brain do not always correlate with cognitive function. Postmortem studies have shown this previously, but in vivo amyloid imaging allows us to explore this phenomenon in ways that were not previously possible. Two opposing conclusions can be drawn from this figure: 1) either fibrillar A deposition is not related to the cognitive dysfunction of AD or 2) there are modulators of the effects of fibrillar A deposition on cognition. To fully understand the pathophysiology of AD, we must address the question: Which factors determine the impact of A deposition in a given individual? Two of the most important diseases in the aging brain are AD and vascular disease. Many studies have shown that vascular disease can contribute to MCI and dementia. This Program Project renewal application proposes to take an integrative view on the inter-relationships between these two disorders and to examine how vascular disease may influence the presence and rate of progression of symptoms in individuals who have AD pathology in their brain. Finding the answer to this important question requires a combination of postmortem studies with in vivo studies to measure A and its potential modulators in close temporal proximity to cognitive testing. We have a unique opportunity to perform postmortem analyses of subjects who underwent PiB-PET imaging and detailed clinical evaluation before death. The overall specific aims of this Program Project are to: 1) Determine whether a combination of A and vascular Modulating Variables (both systemic and cerebrovascular) improves the prediction of the Study Outcomes (i.e., cognition, brain metabolism and atrophy) over A measures alone; and 2) Increase our understanding of the neuropathological substrates of PiB retention and the threshold for in vivo detection of A deposition.